Background <p>[¹⁸F]FDG PET-CT scan has a lower sensitivity in imaging of indolent non-Hodgkin’s Lymphoma (NHL.) We aimed at identifying a threshold of clinical/pathological indicators which would independently predict [¹⁸F]FDG PET-CT scan positivity. For this purpose, we used a retrospective real-world cohort of NHL patients and then validated this criterion on [¹⁸F]FDG and [⁶⁸Ga]Pentixafor scans in a prospective indolent NHL cohort.</p> Results <p>In the retrospective real-world cohort of NHL, Ki67 was identified as an independent factor that influenced [¹⁸F]FDG uptake (<i>r</i> = 0.701). The cutoff value for Ki67 was 36.5% with a maximum area under the curve (AUC) of 0.811 and a Youden index of 0.494 for predicting [¹⁸F]FDG imaging positivity. The sensitivity of [¹⁸F]FDG PET in retrospective NHL cohort was only 65.2% (101/155) which further decreased to 46.3% in patients with Ki 67 ≤ 35%. In the prospective comparison of patients with Ki67 ≤ 35%, [⁶⁸Ga]Pentixafor had a higher sensitivity (80.6% (29/36)) than that of [¹⁸F]FDG PET-CT scan (30.6% (11/36)). However, in patients with Ki67 &gt; 35%, both the imaging modalities had similar sensitivities of 60% (3/5).</p> Conclusion <p>A Ki67 of 35% was shown to be a promising threshold criterion for choosing between [¹⁸F]FDG or [⁶⁸Ga]Pentixafor PET tracer in patients with indolent NHL.</p> Trial registration <p>A Study Evaluating the Value of 68Ga-Pentixafor PET Imaging in the Staging of Hematological Tumor, and Comparing it With 18&#xa0;F-FDG PET/CT Imaging, NCT06834412. Registered 13 February 2025 – Retrospectively registered, <a href="https://register.clinicaltrials.gov/prs/beta/studies/S000FBBP00000062">https://register.clinicaltrials.gov/prs/beta/studies/S000FBBP00000062</a>.</p>